A computational biologist's personal views on new technologies & publications on genomics & proteomics and their impact on drug discovery

Tuesday, September 01, 2015

Ion's S5

The Ion Torrent team rolled out a new sequencer line this morning, the S5. The S5, whose impending release had been tipped on the internet by the leak of a manual, arrives in two models, the standard and the XL, which differ only by on-board computing power and not sequencing metrics. As has been the trend, Ion's focus is entirely on focused sequencing, and the new lineup emphasizes making targeted sequencing with AmpliSeq and other approaches fast and simple.The new instrument, which lists for $65K ($150K for the XL model), sports three new chips, which are not interoperable on either the PGM or Proton; certainly for Ion the concept that all upgrades are encased in the consumable is long dead.. The low-end 520 chip offers performance similar to the PGM 318 chip with 200 or 400bp reads. The mid-range 530 chip offers 3-fold the output of a 318 chip, again with 200 or 400 bp read options. The top-end 540 chip has Proton PI-like characteristics, with only 200bp reads supported. The fact these straddle the two prior systems is underscored by the fact that the 520 and 530 will use the HiQ enzyme for PGM whereas the 540 will use the HiQ enzyme for Proton.

Reagents are loaded on the system as 3 cartridges, each bearing RFIDs for auto-detection of the cartridge type by the instrument. Reagents are shelf-stable for 12 months, simplifying reagent management. Reagents for the 520 and 530 are the same, regardless of which read length is used, again simplifying stocking reagents. If linked to a $55K Ion Chef sample and template preparation robot, as most customers probably will, then amplified DNA can be sequenced with only 45 minutes of hands-on time and as few as two pipetting steps. In 200 bp mode, the chips can generate from 5M to 80M reads in only 2.5 hours. The boxes also require only standard electrical connections; no gas or water connections are required.

Ion sees huge growth opportunities in the targeted sequencing space, starting with their strong position in cancer (with over 100 publications in peer-reviewed journals but branching out into biosurveillance, infectious diseases, food safety, forensics and other areas. Ion's promotional materials emphasize the analytical simplification enabled by targeted panels. This is also where the bigger XL kicks in, able to perform the full on-board analysis (no separate server for either box) in about one third the time of its little sibling.

In the early, heady days of Ion Torrent it was promoted as a disruptive technology that would take on every sequencing challenge. While there are echos of that past in the new presentation, the reality is that Ion has identified a profitable market segment -- those desiring fast, targeted sequencing -- and is going full bore in this area. Ion's focus is on expanding the number of off-the-shelf assay panels available for their instrumentation line while making that line simpler and less labor intensive to operate. While a timetable for FDA clearance was not released, the S5 instruments are clearly aimed at clinical labs.

What about the competition? MiSeq is the only standing competitor with broad appeal, but in its fastest mode takes 4 hours to deliver very short (1x36bp) and only around 500Mb (give or take) of these. The repeated feedback when I write these pieces is that for fast, targeted applications Ion is just better. Potential new entrants such as GnuBio, Genia/Roche and QIAGEN have gone all but silent. Oxford Nanopore would like to tackle this space and could beat Ion on speed (and by a huge amount on cost), but is still shaking out the kinks in their system and tuning up performance, and in any case will have to convince users that the software exists to filter out the noise in nanopore reads (which can be quite good, the trick is knowing which ones are the good ones even amongst 2D reads). So Ion has an opportunity to nail down users before these competitors get out of the starting blocks.

The S5 isn't the uber low-cost Ion instrument I dreamed of earlier this year, but it is interesting to note that a combined S5 + Chef purchase will set you back about $120K (in the U.S.), in the same ballpark as the original all-in price for a PGM system (which was about $100K) -- but this offers far more automation. So while Ion isn't a disruptive technology, it is continuing to refine itself for a key market.

(Note: this entry was prepared using embargoed materials provided by Ion, as well as access to a press presentation which was similarly embargoed).

nice summary. As for the diagnostic setting of clinical genetics looking for germline mutations, I still like the "no homopolymer issue by design" aspect of Illumina. Errors are just not allowed in that field. For somatic mutations in cancer and for bug identification, that is not so much of an issue and as far as I can tell, that's what most Ion users do. These are also the fields that can be time sensitive.

Looking at list prices here in Europe, it seems like run prices don't really change much. 8 runs using Chef with 318 and HiQ come down to 6842.88 Euros, but that's only 200bp, if you need 400bp you have to add 488.16 Euros for the 400 supplies kit.8 runs with 520 are 7390 Euros, but that already includes 400pb. So PGM runs are pretty much same price when looking at basically the same output.

However, there are people who need low output runs, e.g. because they can't wait for more samples to come in. So if a 314 or 316 is all you need, your runs will be substantially cheaper with the PGM.

For those who could use a little more output like very large gene panels, the 530 chip is really what is completely new here. 15-20 million reads is around 4x the 318 chip, while hopefully offering the same quality incl. 400bp reads. Personally, I would have prefered to see this chip as a "320" for PGM, if at all technically possible.

Too bad they still cannot produce quite the same quality incl. 400bp in the higher output arena. That would make e.g. their AmpliSeq Exome kit a lot better. AmpliSeq panels have profited quite a bit from 400bp and HiQ. Less amplicons and higher specificity. Ampliseq is really a large plus for the Ion platform. Works very good, very high coverage and high uniformity.

Handling seems a little easier, but most Ion users will agree that handling of PGM/Proton is not that much of an issue, Templating/loading with Chef was more of a leap forward.

So yes, it is a nice evolution and they clearly target the diagnostics market where things need to be simple and robust. Adding low output chips to the line might be a good idea.

What's Oxford Nanopore sequencing look like on DNA derived from FFPE? Lots of these ion ampliseq panels target tumors preserved with formalin. DNA quality may be a huge challenge for the nanopore devices in the future.

I don't know of any datasets yet from FFPE for MinION -- given its propensity to detect any sort of deviation from standard DNA, straight FFPE may be nightmarish. On the other hand, even limited PCR would generate unmodified copies, so that could be a quick workaround.

Saw a vendor talk at Genome Science 2015 that suggested that FFPE damage can be repaired with a kit from NEB (https://www.neb.com/products/m6630-nebnext-ffpe-dna-repair-mix). It was also suggested it was compatible with long read instruments (maybe not actually generating long reads).

Nick, looks like an interesting product, especially the deamination-of-cytosine-to-uracil- and nicks-and-gaps repair part. But it will not give longer reads, of course.

I don't really see how ONT will be terribly useful in FFPE tumor sample analysis. Maybe handling will be easier, but unless you can afford and do whole genome analysis with it (certainly not with a MinION), you will still need some enrichment, which really is most work (and cost) on any platform. Biggest plus for nanopore sequencing seems to me the ultralong haplotyping. But if you have short fragments to start with, that won't play out. Also, the error rate apparently is still quite high in nanopore sequencing. Especially if you want to look into rare somatic mutations, high error rates are problematic.

About Me

Dr. Robison spent 10 years at Millennium Pharmaceuticals working with various genomics & proteomics technologies & working on multiple teams attempting to apply these throughout the drug discovery process. He spent 2 years at Codon Devices working on a variety of protein & metabolic engineering projects as well as monitoring a high-throughput gene synthesis facility. After a brief bit of consulting, he rejoined the cancer drug discovery field at Infinity Pharmaceuticals in May 2009. In September 2011 he joined Warp Drive Bio, a startup applying genomics to natural product drug discovery. Other recurring characters in this blog are his loyal Shih Tzu Amanda and his teenaged son alias TNG (The Next Generation).
Dr. Robison can be reached via his Gmail account, keith.e.robison@gmail.com
You can also follow him on Twitter as @OmicsOmicsBlog.